Molecular Effect of Exercise

Molecular Effects of Exercise

• Exercise produces signaling molecules in response to muscle contraction, influencing its own metabolism and the metabolisms of other tissues and organs.
• Exercise can induce dynamic remodeling in the cellular composition of tissues and vasculature, affecting data interpretation across multiple omics applications.

Types of Exercise

• Low-Load Endurance Exercise:
  • Characterized by an increase in structures supporting oxygen delivery (capillaries) and consumption (mitochondria).
  • Examples include running, cycling, rowing, swimming, and cross-country skiing.
• High-Load Strength Exercise:
  • Characterized by growth of muscle fibers, primarily through an increase in the amount of contractile proteins.
  • Mitochondria are the cellular organelles that provide much of the energy in our cells.

Mitohormesis

• Adaptive response of cells to intermittent stress, resulting in increased mitochondrial metabolism and reduced reactive oxygen species (ROS).
• Key players in mitohormesis include:
  • Peroxisome proliferator-activated receptor Gamma Coactivator-1alpha (PGC-1), which regulates key genes in skeletal muscles.
  • Nuclear factor erythroid 2-related factor 2 (Nrf2), which activates various genes that encode antioxidant enzymes.

Exercise and Angiogenesis

• Mitochondrial content and capillary content are highly correlated in skeletal muscle.
• Key players in angiogenesis include:
  • Vascular Endothelial Growth Factor (VEGF), which triggers capillary growth.
  • Hypoxia-inducible factor-1 (HIF-1), which induces transcription of target genes involved in erythropoiesis, angiogenesis, glycolysis, and energy metabolism.

Myokines and Exercise

• Skeletal muscle is an endocrine organ that produces signaling molecules (myokines) in response to contraction.
• Myokines influence its own metabolism and the metabolisms of other tissues and organs.
• Examples of myokines include:
  • Interleukin-6 (IL-6), which stimulates both glucose and lipid metabolism.
  • IL-6 promotes hypertrophy by stimulating proliferation of muscle stem cells (satellite cells) and by augmenting the rate of protein synthesis.

Muscle Satellite Cells and Exercise

• Satellite cells are a heterogeneous population of cells that undergo symmetric division and differentiation in response to stimulation.
• Strength training increases skeletal muscle fiber cross-sectional area and satellite cell number.
• Androgens are steroids that promote satellite cell activation and proliferation, further supporting skeletal muscle hypertrophy.

Signal Transduction Pathways in Exercise

• Several kinases are activated in response to exercise, including:
  • Adenosine monophosphate (AMP)-activated protein kinase (AMPK)
  • Protein kinase A (PKA)
  • Calcium/calmodulin-dependent protein kinase (CaMK)
  • Mitogen-activated protein kinase (MAPK)
  • Protein kinase C (PKC)
  • Mammalian target of rapamycin (mTOR)
• AMPK activation through physical exercise improves mitochondrial biogenesis through the regulation of PGC-1α.
• CaMK-II promotes lipid uptake and oxidation, and skeletal muscle also triggers regulation of important transcription factors, such as the cyclic AMP response element-binding protein (CREB), MEF2, and HDACs.

Differences in Molecular Responses to Exercise

• Endurance training activates the AMPK-MAPK-PGC-1α signaling cascades, leading to increased mitochondrial biogenesis and metabolic adaptations.
• Resistance training increases the activation of the phosphoinositide 3-kinases Protein kinase B–mTOR (PI3k-Akt-mTOR) signaling cascade, regulating the rate of protein synthesis and/or degradation and consequently, muscle hypertrophy.

Epigenetics of Exercise

• Epigenetics is the study of changes in transcriptional expression and/or activity without variation in DNA sequence.
• Epigenetic modifications include:
  • DNA methylation
  • Histone modifications (acetylation, methylation, phosphorylation, lactylation)
  • Micro-RNAs

DNA Methylation

• DNA methylation results in the stable silencing of gene expression by repressing transcription.
• Exercise generally results in DNA hypomethylation in key skeletal muscle genes, representing an early response that mediates skeletal muscle adaptations to exercise.

Histone Modification

• Histone acetylation is a transient enzymatic process that is associated with gene activation.
• Histone methylation can activate or repress gene transcription depending on the proteins they recruit to chromatin.
• Histone phosphorylation occurs at the serine and tyrosine residues of histones, and is involved in phosphorylation-dependent signaling during exercise.

Micro-RNAs

• Micro-RNAs are small non-coding RNAs that generally repress the expression of several genes at a post-transcriptional level.
• MyomiRs (micro-RNAs arising from skeletal or cardiac muscle) have been identified, including miR-1, miR-133a, miR-133b, miR-206, miR-208b, miR-486, and miR-499.
• MyomiRs' functions are to control the biogenesis, regeneration, and maintenance of the skeletal muscle tissue.